Insulin resistance is a pathological condition that insulin resistance decreases in tissues and especially in type II diabetes, is a major cause associated with the development or progress of diabetes, in addition to impaired insulin secretion. In general, many patients with diabetes accompanying obesity have insulin resistance. Thus, insulin resistance is considered to be deeply involved in obesity. It is further known that insulin resistance is observed not only in diabetes but also in disorders caused by abnormalities in lipid metabolism such as arteriosclerosis, etc. (Saltiel, A. R., Cell, 104, 517-529, 2001).
While the mechanism of insulin resistance largely remains unknown yet, a suggestion, as one point of view, is made on a similarity to the mechanism of inflammation in animal test or on an experimental level using a culture cell system. For example, it is reported that when lipopolysaccharide (LPS) was administered to pregnant rats, the offspring were found to develop obesity and insulin resistance at adult age (Nilsson et al., Endocrinol., 142, 2622-2630, 2001); TNF-α, which is one of inflammatory cytokines, is produced and/or secreted more in obese adipocytes to inhibit the action of insulin (Hotamisligil G. S. et al., Science, 259, 87-91, 1993); moreover, thiazolidine derivatives, which are insulin-sensitizing agents, have an anti-inflammatory action (Pasceri, V. et al., Circulation, 101, 235-238, 2000) and so on. Furthermore, fluctuation in expression of several proteins associated with inflammatory reactions, including LPS-binding protein are noted also in ob/ob mice as obesity model mice (Soukas, A. et al., Genes Develop, 14, 963-980, 2000).
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane protein of one transmembrane type belonging to the immunoglobulin superfamily found to be a homolog protein of TREM-1 thought to be involved in inflammatory reactions (Bauchon, A. et al., J. Immunol., 164, 4991-4995, 2000, Daws M. R. et al., Eur. J. Immunol., 31, 783-791, 2001). TREM-1 is abundantly expressed on neutrophils and on monocytes. It is known that its expression results in amplifying inflammation by promoting the secretion of lipopolysaccharide-induced TNF-α or interleukin-1β and by inhibiting the expression, acute inflammatory response can be suppressed in mice (Bauchon, A. et al., Nature, 410, 1103-1107, 2001). It is reported that TREM-2 interacts with DAP12 as in TREM-1 to effect signal transduction (Daws M. R. et al., Eur. J. Immunol., 31, 783-791, 2001); TREM-2 induces the expression of CC chemokine receptor 7 (CCR7) in dendritic cells or macrophages to take part in maturing of dendritic cells (Bouchon, A. et al., J. Exp. Med., 194, 1111-1122, 2001); and TREM-2 is associated with NO production (Daws M. R. et al., Eur. J. Immunol., 31, 783-791, 2001).
Safe and excellent pharmaceuticals for sensitizing insulin have been earnestly awaited.